Project Summary: Normally, glutamatergic synapses in the mature brain predominantly express GluA2-containing Ca2+- impermeable AMPARs. However, certain synapses, such as the synapses between hair cells and cochlear afferents, also express GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs). In the parent R01: EXCITATION AND EXCITOTOXICITY IN TYPE I COCHLEAR AFFERENTS: SYNAPTIC STRUCTURE AND FUNCTION, we published on the presence of GluA2-lacking AMPARs in rat cochlea and proposed that those receptors are Ca2+- permeable as is the case in hair cell organs from frog and zebrafish. We recently submitted a paper on GluA2- lacking CP-AMPARs in synaptopathic excitotoxicity in the mouse cochlea. Notably, certain neuropathologies are known to involve CP-AMPARs, including epilepsy, ischemia, traumatic brain injury, and addiction/withdrawal. Work on the parent R01 is focused on the hypothesis that CP-AMPARs contribute to induction of neurodegeneration. Other recent work on Alzheimer's Disease has implicated CP-AMPARs in progressive, selective neurodegeneration in the brain. The proposed studies will examine a possible link between cochlear synapses and neurodegeneration in Alzheimer's disease. The cellular mechanisms responsible for neuronal pathology in Alzheimer's disease (AD) remain poorly understood. Our project is motivated by the observation that two of the key genes and proteins in AD, amyloid precursor protein (APP) and Tau are highly expressed in the sensory tissues of the inner ears of mice. In addition, studies of human populations indicate that auditory and vestibular deficits are associated with the development of AD. Based on these observations, we hypothesize that AD may contribute to neurodegeneration in the inner ear through changes in synaptic molecular anatomy and Ca2+-permeability of AMPARs. A more complete understanding of how AD affects the inner ear may lead to novel diagnostics for the detection of early stage AD in humans. Moreover, understanding the basic and pathological functions of AD proteins in the inner ear may shed light on AD mechanisms in the brain. Specific Aim 1 will determine the expression of AMPAR subunits at inner ear synapses in mouse models of AD. Specific Aim 2 will measure inner ear function in mouse models of AD. Together, the proposed experiments will determine whether AD mouse models have molecular changes at inner ear synapses and if they associate with changes in hearing or vestibular function. If synaptic dysfunction and nerve degeneration in the ear involve processes similar to AD processes in the brain, then we should further study AD mechanisms in the ear. Insights and tools from AD research will be applied in the ear to prevent loss of hearing and balance function, and may also assist in a more complete understanding of AD neuropathology in the brain.